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Condensins Exert Force on Chromatin-Nuclear Envelope Tethers to Mediate Nucleoplasmic Reticulum Formation in Drosophila Melanogaster

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Condensins Exert Force on Chromatin-Nuclear Envelope Tethers to Mediate Nucleoplasmic Reticulum Formation in Drosophila Melanogaster INVESTIGATION Condensins Exert Force on Chromatin-Nuclear Envelope Tethers to Mediate Nucleoplasmic Reticulum Formation in Drosophila melanogaster Julianna Bozler,* Huy Q. Nguyen,* Gregory C. Rogers,† and Giovanni Bosco*,1 *Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, and †Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724 ABSTRACT Although the nuclear envelope is known primarily for its role as a boundary between the KEYWORDS nucleus and cytoplasm in eukaryotes, it plays a vital and dynamic role in many cellular processes. Studies of nuclear nuclear structure have revealed tissue-specific changes in nuclear envelope architecture, suggesting that its architecture three-dimensional structure contributes to its functionality. Despite the importance of the nuclear envelope, chromatin force the factors that regulate and maintain nuclear envelope shape remain largely unexplored. The nuclear nucleus envelope makes extensive and dynamic interactions with the underlying chromatin. Given this inexorable chromatin link between chromatin and the nuclear envelope, it is possible that local and global chromatin organization compaction reciprocally impact nuclear envelope form and function. In this study, we use Drosophila salivary glands to nuclear envelope show that the three-dimensional structure of the nuclear envelope can be altered with condensin II- mediated chromatin condensation. Both naturally occurring and engineered chromatin-envelope interac- tions are sufficient to allow chromatin compaction forces to drive distortions of the nuclear envelope. Weakening of the nuclear lamina further enhanced envelope remodeling, suggesting that envelope struc- ture is capable of counterbalancing chromatin compaction forces. Our experiments reveal that the nucle- oplasmic reticulum is born of the nuclear envelope and remains dynamic in that they can be reabsorbed into the nuclear envelope. We propose a model where inner nuclear envelope-chromatin tethers allow inter- phase chromosome movements to change nuclear envelope morphology. Therefore, interphase chromatin compaction may be a normal mechanism that reorganizes nuclear architecture, while under pathological conditions, such as laminopathies, compaction forces may contribute to defects in nuclear morphology. During the past several decades we have begun to appreciate the DNA damage repair, and response to mechanosensory inputs (De structural and functional complexity of the nuclear envelope. Although Vosse et al. 2011; Maniotis et al. 1997; Therizols et al. 2006). The primarily known for its role in the partitioning of genomic and tran- well-described physical structures of the double membrane layer and scriptional components away from the cytoplasm, the nuclear envelope nuclear structural filaments, such as nuclear lamins, remain the pre- plays a vital and dynamic role in gene expression, signal transduction, dominant platforms for interaction between chromatin and the cyto- plasm (Shimi et al. 2012). These two membrane layers are connected Copyright © 2015 Bozler et al. through integral membrane proteins and are punctuated with the doi: 10.1534/g3.114.015685 nuclear pore complex that facilitates bidirectional macromolecule Manuscript received November 12, 2014; accepted for publication December 22, movement between nucleoplasm and cytoplasm. The internal struc- 2014; published Early Online December 30, 2014. tural support of the nucleus is provided in large part by the nuclear This is an open-access article distributed under the terms of the Creative Commons Attribution Unported License (http://creativecommons.org/licenses/ lamina, a meshwork of lamin A- and B-type polymers. Studies of by/3.0/), which permits unrestricted use, distribution, and reproduction in any nuclear structure have exposed tissue- specificchangesinthe medium, provided the original work is properly cited. threee-dimentional architecture of the nuclear envelope, revealing in- Supporting information is available online at http://www.g3journal.org/lookup/ tricate patterns of tunneling and branching of the nuclear envelope suppl/doi:10.1534/g3.114.015685/-/DC1 1Corresponding author: Department of Genetics, Geisel School of Medicine within the nuclear space (Dupuy-Coin et al. 1986; Fricker et al. 1997). at Dartmouth, 7400 Remsen, Hanover, NH 03755. E-mail: Giovanni. This higher order arrangement of the nuclear envelope has been given [email protected] the name nucleoplasmic reticulum (NR) (Malhas et al. 2011). The Volume 5 | March 2015 | 341 importance of these NR structures for chromosome partitioning, nu- Cytoskeletal forces have been studied in the context of nuclear clear transport, gene expression, or other cellular processes are not architecture (Maniotis et al. 1997), but the role of chromatin has only well understood. Although we lack a comprehensive understanding of begun to be implicated in the mechanical stabilization of nuclear the functional role of nuclear architecture, it has become clear that the architecture. Recent studies have revealed that decondensation of chro- nuclear envelope and its three-dimensional shape can profoundly matin directly leads to a mechanically destabilized nucleus (Mazumder impact genome organization and gene expression (De Vosse et al. et al. 2008). Additionally, it has been shown that chromatin acts as 2011; Schneider and Grosschedl 2007). a force-bearing element in the unchallenged nucleus (Dahl et al. 2005). The typical interphase genome is radially organized with hetero- This has led to the supposition that nuclear and cytoplasmic anchors chromatin and transcriptionally silent gene regions predominantly are important contributors to the structural integrity of the nucleus. restricted to the nuclear periphery (Hochstrasser and Sedat 1987; Further, it has been suggested that chromatin-envelope interactions Rajapakse and Groudine 2011). However, exceptions to this trend constitute a mechanical scaffold that defines and preserves nuclear exist. For example, nuclear pore complexes can recruit and tether architecture (Mazumder and Shivashankar 2007; Mazumder et al. ı transcriptionally active genes (Capelson et al. 2010; Rodr guez- 2008). Mounting evidence suggests that mechanical forces within the Navarro et al. 2004). These observations have led to a model in which nucleus may have an equally profound effect on nuclear structure and association with the nuclear envelope serves as a boundary between yet remain relatively enigmatic (Buster et al. 2013; George et al. 2014). active and inactive chromatin (Bermejo et al. 2011; Blobel 1985). Importantly, dynamic forces exist within the nucleus, not only in Other models propose that chromatin tethers to the nuclear envelope preparation for cell division, but during interphase as well. The serve to organize chromosomes into distinct territories (Bauer et al. condensin complexes are recognized as regulators of chromatin 2012; Verdaasdonk et al. 2013). Regardless of the functional role structure and topology during cell division, with condensin II chromatin-envelope interactions may have, it is clear that chromatin maintaining activity during interphase. Shared between condensin I is tethered to the inner nuclear envelope through a variety of DNA- and condensin II is the SMC2/4 heterodimer, endowing the complex protein and protein-protein interactions (Dahl et al. 2005; Gruenbaum with its essential ATPase domains (Kimura and Hirano 1997). Unique et al. 2005; Mazumder et al. 2008). Chromatin interacts with the to condensin II are the chromosome-associating protein subunits nuclear envelope through contacts with the nuclear lamins or the Cap-D3, Cap-H2, and Cap-G2, the regulation of which likely confers nuclear pore complex (Ye et al. 1997). Lamins bind chromatin through fi interphase activity (Buster et al. 2013; Hartl et al. 2008; Hirano et al. interactions with histones or by directly binding sequence-speci c 1997). During interphase, condensin II participates in the mainte- regions of DNA termed matrix-attachment regions (Zhao et al. nance of chromosome territories and drives homolog unpairing 1996). These chromatin-envelope tethers facilitate gene regulation (Bauer et al. 2012; Hartl et al. 2008). Hyperactivation of condensin as well as genome organization (Dialynas et al. 2010; Therizols et al. II, either by inactivation of the negative-regulator SCFSlimb or by over- 2006; Verdaasdonk et al. 2013). expression of Cap-H2, results in dramatic chromosome condensation, Given the substantial role of the nuclear envelope in genome suggesting that dynamic chromatin movements occur during inter- regulation, it is not surprising that defects in nuclear architecture are phase and that these movements are induced by condensin II activity linked to a variety of diseases. There are 12 known disorders that arise (Bauer et al. 2012; Hartl et al. 2008). Similarly, loss of condensin II from mutations in the A-type lamins and lamin-associated proteins, function leads to lengthening of interphase chromosomes (Bauer et al. such as Emery-Dreifuss muscular dystrophy and Hutchinson-Gilford 2012). Therefore, condensin II could be seen as more broadly regu- progeria syndrome (Goldman et al. 2004; Sullivan et al. 1999). In these lating the mechanical properties of chromatin mediated support of the syndromes, the characteristic deformation of the nuclear envelope results in a loss of peripheral heterochromatin, altered gene expression nuclear envelope. Notably,
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